Rapamycin increases cerebral blood flow and modulates metabolic, inflammatory, and microbiome profiles in healthy middle-aged APOE4 carriers: a pilot single-arm trial.

Aware C, Neher CM, Woods C, Khegai O, Dwivedi AK, Govindarajan M, Ivanich K, Kurt M, Beversdorf D, Cheng J, Bresette N, …, Lin AL · 2026 · Journal of Cerebral Blood Flow and Metabolism · Atlas ID AWARE2026

What this study shows

Single-arm pilot trial: 1 mg/day rapamycin for 4 weeks in 23 cognitively normal adults aged 45 to 65. Cerebral blood flow rose by more than 15% across several brain regions in the nine APOE4 carriers, while non-carriers showed no significant change; metabolic and inflammatory profiles improved and the gut microbiome was modulated. Uncontrolled, small and genotype-specific, so this is early evidence only.

Abstract

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Carriers of the apolipoprotein E4 (APOE4) allele often develop cerebrovascular dysfunction and broader systemic alterations decades before the onset of Alzheimer's disease (AD) pathology or clinical symptoms. Early interventions that can improve these functions may help delay or slow AD progression. In this study, we repurposed rapamycin (sirolimus), an FDA-approved medication with anti-aging properties, to target APOE4 associated multisystem dysfunction.

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At a glance

Evidence type	H Human study Marked H because it is direct evidence from a human clinical trial or human cohort; the code names the kind of study, not its quality -- a small, well-run trial is still H.
Study type	2 - Human Clinical Trial
Model system	Human pilot single-arm trial, healthy middle-aged APOE4 carriers vs non-carriers
Journal	Journal of Cerebral Blood Flow and Metabolism
Year	2026
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1177/0271678X261490342 · PMID 42723264

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Low-dose rapamycin (sirolimus) 1 mg/day for 4 weeks
Target	mTORC1 (systemic), with cerebral blood flow as primary readout
Model	Human (cognitively normal adults 45-65, APOE4 carriers vs non-carriers)
Effect	Increased cerebral blood flow (>15% across multiple regions) and improved metabolic/inflammatory profiles in APOE4 carriers only; genotype-dependent, uncontrolled pilot.

In the Atlas

Open questions that cite this study

Cited as supporting evidence for the open question Brain-penetrant mTOR inhibition clears aggregates in models, but human dosing has not been shown to reach the brain — and mTORC2 is needed for memory in mice.

Cite this paper

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Aware, C., Neher, C. M., Woods, C., Khegai, O., Dwivedi, A. K., Govindarajan, M., Ivanich, K., Kurt, M., Beversdorf, D., Cheng, J., Bresette, N., Cui, T., Balchandani, P., Gonzales, M. M., Ericsson, A. C., Altes, T. A., & Lin, A. L. (2026). Rapamycin increases cerebral blood flow and modulates metabolic, inflammatory, and microbiome profiles in healthy middle-aged APOE4 carriers: a pilot single-arm trial. Journal of Cerebral Blood Flow and Metabolism. https://doi.org/10.1177/0271678X261490342

@article{AWARE2026,
  author       = {Aware, C. and Neher, C. M. and Woods, C. and Khegai, O. and Dwivedi, A. K. and Govindarajan, M. and Ivanich, K. and Kurt, M. and Beversdorf, D. and Cheng, J. and Bresette, N. and Cui, T. and Balchandani, P. and Gonzales, M. M. and Ericsson, A. C. and Altes, T. A. and Lin, A. L.},
  title        = {{Rapamycin increases cerebral blood flow and modulates metabolic, inflammatory, and microbiome profiles in healthy middle-aged APOE4 carriers: a pilot single-arm trial}},
  journal      = {Journal of Cerebral Blood Flow and Metabolism},
  year         = {2026},
  doi          = {10.1177/0271678X261490342},
  note         = {PMID: 42723264},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record AWARE2026) [Data set]. https://mtor-atlas.org/study/AWARE2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_AWARE2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record AWARE2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/AWARE2026/},
  doi          = {10.5281/zenodo.22059963}
}

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